While published reports on seizure outcomes following epilepsy surgery have occupied centre stage world-wide, ever since the work of Penfield and Jasper made epilepsy surgery a therapeutic option, the last decade has seen a shift in focus onto a more nuanced and objective approach to outcome assessment beyond seizure control. Several aspects of assessment of patients with pharmaco-resistant surgically treatable epilepsy, however, deserve attention in order to improve our understanding of the causation, course as well as freedom from seizures, and the health impact on quality of life. The study by Chaturvedi et al., in this issue, highlights one such important aspect.[1] The authors report the overall impact of epilepsy surgery on seizures as well as on the quality of life, in a select population of individuals with epilepsy associated with focal cortical dysplasias.

In their most recent study, Lunney et al., adopted a systematic approach towards identification of various factors that are important to patients while assessing their satisfaction with epilepsy surgery.[2] They combined information from focused group discussions with epilepsy surgery patients as well as from expert opinion (through the Delphi consensus methodology) and developed a list of 31 items on 12 themes related to ‘patient satisfaction’. Through a prospective study, Shukla et al., evaluated the role of various non-seizure determinants of post-epilepsy-surgery quality-of-life among 37 persons with epilepsy (PWE),26 of whom were seizure-free following surgery.[3] Among these 26 patients, a significantly higher proportion of PWE with poor memory scores, those without improvement in social status (education, employment, marital prospects or harmony and stigma), and those with co-morbid anxiety or depression, formed the sub-group with poor quality-of-life scores. Current studies on epilepsy surgery outcomes try to include details of post-surgical quality-of-life more frequently. It is evident that evaluating success of the intervention (surgery) is based on several additional factors, apart from seizure freedom or reduction. This is understandable, since seizures are associated with an array of co-morbidities among patients with epilepsy. In a population survey from the U.S., 2% of 172,959 adult respondents reported having been diagnosed with epilepsy, who in turn were found significantly more likely than those without epilepsy, to report neuropsychiatric co-morbidities (anxiety, depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), sleep disorder, movement disorder) as well as pain disorders and asthma.[4]

While quality-of-life in epilepsy (QOLIE 31) and the QOLIE 89 inventory have been the most widely used tools for the overall assessment of quality-of-life among patients with epilepsy, there is a need to develop and refine a comprehensive tool specifically for patients undergoing epilepsy surgery, incorporating important parameters consistently found to impact patient satisfaction and quality-of-life. To elaborate on the possible inadequacy of the available tools, as an example, the detailed QOLIE 89 inventory (also used in the study by Chaturvedi et al., in this issue), the study does not assess sleep quality at all, while questions on sexual relations and driving may not necessarily apply to all patients undergoing epilepsy surgery (especially in those with refractory epilepsy and frequent comorbidities), and scoring these may result in misleading impressions or conclusions.

Thus, one cannot emphasize enough the need to report on the comprehensive evaluation of epilepsy surgery outcomes that include subjective as well as objective assessment of neuropsychiatric, cognitive, social and medical parameters, in addition to seizure reduction.

Malformations of cortical development form a large subset among patients with pharmaco-resistant epilepsy, often benefitting from surgical treatment. Far greater focus has remained on the commoner subset of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis, (pertaining to risk factors, etiopathogenesis, response to various treatment strategies and co-morbidities or post- surgical complications) undergoing surgery. Clinical studies on malformations of cortical development are, however, mostly limited to case series reporting surgical outcomes in terms of seizure freedom, or cognitive outcomes.[5] A few studies have presented a definitive overview of different etiological risk-factor-related and clinical- course-related characteristics.[6] Most literature on epilepsy surgery outcomes remains location specific – temporal and extratemporal (even insular, cingulate and other locations, to be more specific). On analysis of predictors of surgical outcome, many general factors like age at onset and duration of epilepsy are analysed. Etiology may also often be included in the comparison of good versus poor outcomes. However, the predictors of outcome among different etiological categories are likely to vary significantly. Hippocampal sclerosis has a unique position among the common etiological categories, to the extent that risk factors among patients may be similar in terms of the initial precipitating events (antecedents); but also, more importantly, in terms of a common anatomical substrate for the epileptogenic focus. Malformations of cortical development or even the narrow subset of focal cortical dysplasias (FCDs), in contrast, have a totally variable anatomical localization, hence possibly also, pathological substrates, with variable susceptibility to seizure induced damage as well as response to surgical resection. Recent evidence does support some anatomical predisposition of seizures related to the subtypes of FCD: type 1 being more common in temporal lobe epilepsy, and type 2 being more common in extratemporal locations.[7] There is a growing evidence in favor of a role for both intrinsic genetic as well as environmental factors in causing disruption of cortical development. An example for genetic influence is the detection of DEPDC5 (dishevelled, egl-10 and pleckstrin domain-containing 5) mutations among families with FCD and focal non-lesional epilepsy.[8] Evidence supporting an extrinsic (infective – viral) influence may be available from polymerase chain reaction (PCR) studies on brain specimens of patients who have been suffering from FCD type II, who have tested positive for human papilloma virus 16 (HPV16) deoxyribose nucleic acid (DNA) and ribose nucleic acid (RNA).[9] While these studies bring forth valuable information, prospective clinical studies assessing children born to pregnant women with a family history of focal epilepsy secondary to malformations of cortical development; or, to those children identified with viruses with a possible etiological role (human papilloma virus as well as TORCH [Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus, Herpes simplex) infections, compared to those with none of these, could yield information which is yet unavailable. Association of maternal Zika virus infection with congenital brain abnormalities, including many malformations of cortical development, has added a significant amount of information to correlate evidence linking infection as an environmental factor with the causation of severe brain malformations.[10] Research focussed on exploring the link between other environmental (microwave radiation, chemical pollutants, and teratogens) as well as genetic factors could potentially lead to clinical categorization of patients with focal cortical dysplasias and add to the broadening of risk factor analysis for etiology specific epilepsy surgery outcomes.

With attention to analysis of ‘more than seizure outcome’ following epilepsy surgery for particular etiological categories like focal cortical dysplasias, studies like that by Chaturvedi et al., aid in moving the clock forward on a wider understanding of a large number of under-investigated aspects of pharmaco-resistant focal epilepsy. Future directions for epilepsy outcomes research will no doubt focus on the increasing recognition of epilepsy as a wider network disorder in the brain; and, FCDs may represent only the visible tip of the iceberg. Therefore, additional information using rapidly evolving imaging technologies that will shed additional light on the link between focal dysplasias and the wider neuronal network in epilepsy, will also identify the anatomical and functional underpinning of factors that impact epilepsy related quality-of-life.